3beta-fluoro-delta5-9beta, 10alpha-pregnen-20-one and derivatives thereof



ilrrit tet Patented Jan. 1, 1963 Free 3,071,603 3,8-FLUUR-A-9fi,10a-PREGNEN-20-0NE AND DERIVATIVES THEREOF John A. Zderic, PaloAlto, Calitl, and Otto Halpern and Jose lriarte, Mexico City, Mexico,assignors, by mesne assignments, to Syntex Corporation, a corporation ofPanama No Drawing. Filed Jan. 31, 1962, Ser. No. 170,268 19 @Zlaims.(Cl. 260-397.3)

$Hz-Y on X I I In the above formula X represents fluorine, chlorine orbromine; Y may be hydrogen, fluorine, hydroxy or an acyloXy group; and Rrepresents hydrogen, hydroxy or an acyloxy group.

The acyloxy groups are derived from hydrocarbon car boxylic acidscontaining less than 12 carbon atoms which may be saturated orunsaturated, of straight, branched, cyclic or cyclic-aliphatic chain,aromatic, and may be substituted by functional groups, such as hydroxy,alkoxy containing up to 5 carbon atoms, acyloxy containing up'to 12carbon atoms, nitro, amino or halogen. Typical ester groups are theacetate, propionate, enanthate, benzoate, trimethylacetate,t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and,fl-chloropropionate.

The novel compounds of the present invention are prepared by the processpartially represented by the following formula scheme:

TH; CH3 /0 on, 5 CH3 \OJ (l i I /I i/I I H W P I H H1 H0 r E 0:0 0:0eHZAI ore/\I I I H V I H VII X HO CHaZ CH i=0 =o e Id I H v: I H VIII XX CHzZ (1:0 Q -OA i I I H IX X In the above formulas X has thehereinbefore described meaning, Ac represents the acetyl group and Zrepresents iodine, fluorine or acetoXy.

In practicing the process outlined above, the starting A-9,3,l0u-pregnadien-3fi-ol-20-one (I) is conventionally treated withethylene glycol in the presence of an acid, to give20-cycloethylenedioxy-A -9/8,10a-pregnadien-3/3-o1. Oppenauer oxidationof the latter compound afiords 20- cycloethylenedioxy A9fi,l0a-pregnadien-3-one (II). The N-double bond of this derivative isshifted to the A cqnjugated position by treatment in a basic medium, to

free hydroxy compounds.

give the corresponding M' -derivative (III). Reduction of the lattercompound with an alkali metal, preferably lithium, in liquid ammonia,yields ZO-cycloethylenedioxy- A -9fi,l0a-pregnen-3B-ol which uponconventional treatment in a mild acid medium affords A-9,B,lOa-pregnen-3;8- ol-20-one (IV). The latter compound upon treatmentwith a suitable halogenating agent such as hydrogen fluoride, phosphoruspentachloride or phosphorus pentabromide, in a solvent inert to thecorresponding reagent, yields respectively the 3/3-fluoro, 3f3-chloro orBB-bromo 13 -95,10rx-pregnen-20-one (V). Treatment of a 3-haloderivative selected from the latter group with calcium oxide and iodine,in a suitable solvent such as methanol and tetrahydrofuran yields thecorresponding 3fi-halo-21- iOdO-A 9[3,IOot-PIGgHEIl-ZO-Ol'lfi (VI:Z=iodo) which is alternately converted into the corresponding 21-fluoroderivative (VI: Z=fluoro) by treatment with a metal fluoride, preferablysilver fluoride, and into the corresponding 21-acetoxy derivative (VI:Z=acetoxy) by reaction with an alkali metal acetate such as potassiumacetate.

Following a second series of reactions A -9l3,lOot-pregnen-3fi-ol-20-one(IV) is submitted to the Gallagher treatment, i.e. the said compound istreated with acetic anhydride in the presence of p-toluenesulfonic acidto give 3fi,20-diacetoxy-A -9,B,IOaregnadiene, which upon reaction with2.2 molar equivalents of an organic peracid, preferably perbenzoic acid,in an inert solvent such as benzene, yields a mixture of3B,20-diacetoxy-5u,6u; 17a,20a-bis-oxido-9,6,l0apregnane and the5B,6B-oxido isomer thereof; this mixture upon reaction in a mild basicmedium gives a mixture consisting of 50,6ot-OXidO-9fl,l0otpregnane-SB,l7a-diol-20-one and the 5fl,6fl-oxido isomer thereof whichupon treatment under Cornforth' conditions, i.e. with sodium iodide,sodium acetate and zinc dust, in acetic acid, for a period of time ofthe order of 6 hours, yields 13 -95,lot-pregnene-3fl,l7a-diol-20-one.Conventional acetylation of this compound with acetic anhydride in thepresence of p-toluenesulfonic acid, followed by selective saponificationof the 3B-acetoxy group of the resulting 3,17-diacetate, furnishes A-9/3,10 x-pregnene 35,170 diol-20-one-17-acetate (VII). The lattercompound is treated with a suitable halogenating agent such as hydrogenfluoride, phosphorus pentachloride or phosphorus pentabromide, in asolvent inert to the used reagent, to yield the respective 'Jfl-fluoro,3fi-chloro or 3 8-bromo 17a-acetoxy-A -9fi,l0upregnen-20-one (VIII).Treatment of one of these 3,8-11alo compounds with calcium oxide andiodine, in a suitable solvent, preferably methanol and tetrahydrofuran,furnishes the corresponding 3,8-halo-21-iodo 17a acetoxy-A-9fl,10a-pregnen-20- one (IX: Z=iodo). The latter compound isalternately transformed into the corresponding Zl-fluoro derivative (IX:Z=fluoro) by reaction with a metal fluoride, preferably silver fluoride,and into the corresponding 21- acetoxy derivative (IX: Z=acetoxy) bytreatment with an alkali metal acetate such as potassium acetate.

The compounds obtained by the heretofore described process having a 17mand/or 2l-acetoxy group present in the molecule, upon conventionalsaponification in a basic medium, yield the corresponding 17aand/ or 21-The 1711- and 21-hydroxyl groups of the latter compounds areconventionally reesterified in the presence of p-toluenesulfonic acidwith an acylating agent, such as an anhydride derived from a hydrocarboncarboxylic acid of the type hereinbefore defined.

Selective esterification of the 2l-hydroxyl group takes place when theoperation is conventionally conducted in pyridine and in the absence ofp-toluenesulfonic acid.

The following specific examples serve to illustrate, but should not beconstrued as a limitation to, the present invention.

xample I A mixture of 5 g. of A -9fl,10a-pregnadien-3B-ol-20- one[Rappoldt et al., Rec. Trav. Chim., 80, 43 01961)],

150 cc. of anhydrous benzene, 60 cc. of ethyleneglycol distilled oversodium hydroxide and 800 mg. of p-toluene sulfonic acid monohydrate wasrefluxed for 12 hours with the use of an adapter for the continuousremoval of the water formed during the reaction. Aqueous sodiumbicarbonate solution was added to the cooled mixture and the organicphase was separated, washed with water, dried over anhydrous sodiumsulfate and evaporated to dryness. The residue crystallized fromacetone-hexane to give 20-cycloethylenedioxy-A -95, l 0u-pregnadien-3fi-ol.

Example 11 A solution of 4 g. of the latter steroid in 280 cc. oftoluene and cc. of cyclohexanone was dried by distilling off 10 cc. ofthe solvent. A solution of 4 g. of aluminum isopropoxide dissolved in 28cc. of anhydrous toluene was then added and the mixture was refluxed for45 minutes; 12 cc. of acetic acid were added and the solvents removed bysteam distillation. The product was extracted several times with ethylacetate and the organic extracts washed with 5% hydrochloric acidsolution, water, 10% sodium carbonate solution and water until neutral,dried over anhydrous sodium sulfate and evaporated to dryness.Crystallization from acetone-hexane afforded 20-cycloethylenedioxy-A-9fl,10ot-pregnadien-3- one. 7

Example III A solution of 0.17 g. of potassium hydroxide in 0.2 cc. ofwater and 2.5 cc. of methanol was added over 30 minutes to a boilingsolution of 4 g. of the above compound in cc. of methanol under anatmosphere of nitrogen. Boiling was continued for a further 2 hours andthe solution was then cooled, neutralized with acetic acid andconcentrated under reduced pressure. followed by crystallization of theprecipitated solid from acetone-hexane, produced 20-cycloethylenedioxy-A-95, 10a-pregnadien-3-one.

Example IV A solution of 3 g. of the above compound in 60 cc. ofdioxane-ether 1:1) was added in a steady stream to a solution of 0.6 g.of lithium in 800 cc. of anhydrous liquid ammonia with good stirring. Atthe end of the addition the blue color was discharged by the addition of15 g. of ammonium chloride and the ammonia was allowed to evaporate. Theproduct was extracted with ether, washed with water, dried and the etherevaporated to afford a gum which was adsorbed from 300 cc. of benzeneonto g. of alumina. Elution with benzene-ether afforded a product whichupon recrystallization from acetone-hexane gave ZO-cycloethylenedioxy-A-9B,lOa-preguen-Bdol.

Example V 3 g. of the above compound were dissolved in 150 cc. ofacetone and treated with 250 mg. of p-toluenesulfonic acid, the reactionmixture was kept at room temperature overnight. It was then poured intoice water, extracted with ethyl acetate and the organic extract washedwith water to neutral, dried and evaporated to dryness. Addition ofether gave A -913,lOu-pregnen-Bfl-ol-ZO-one.

Example VI In a polyethylene flask, adapted with magnetic stirrer, therewere dissolved 2.8 g. of the foregoing compound in 30 cc. of methylenechloride, the solution was cooled to 0 C. and a solution of 12 g. ofanhydrous hydrogen fluoride in 20 cc. of tetrahydrofuran cooled in aDry-Ice acetone bath (-70 C.) was added over a period of 20 minutes withconstant stirring. .The mixture was stirred at a temperature lower than10 C. for 6 additional hours, then neutralized by cautiously adding a 5%aqueous sodium bicarbonate solution and transferred to aseparatoryfunnel. The organic layer was washed with water, dried over anhydroussodium sulfate and concentrated until formation of an abundantprecipitate. The mixture was cooled, the precipitate filtered and redis-Addition of water,

solved in hot ethyl acetate, the insoluble material was filtered oil.and the filtrate cooled whereby there crystallized 3fi-flu0ro-A -9B,lOa-pregnen--one.

Example VII To a solution of 5 g. of A -9,8,1Oa-pregnen-3,3-ol-20- one,in 100 cc. of benzene were added 5 g. of phosphorus pentachloride andthe resulting mixture was re fluxed for 1 hour in the absence ofmoisture. It was then cooled, poured into water; the benzene layer waswashed with water several times, dried over anhydrous sodium sulfate andevaporated to dryness. Crystallization of the residue fromacetone-hexane yielded 3,8-chloro- A -9,B,10a-pregnen-20-one.

Example VIII Following the procedure described in the foregoing example,except that phosphorus pentachloride was substituted by phosphoruspentabromide, there was obtained 3,8-bromo-A -9B,l0a-pregnen-20-one.

Example IX A mixture of 6.6 g. of A -9,B,10oc-pregnen-3B-ol-20- one, 2.7g. of p-toluenesulfonic acid and 300 cc. of acetic anhydride wassubmitted to a slow distillation; during 5 hours. The residue was cooledand poured into iced Water. The product was then extracted with ether,the extract washed successively with an aqueous solution of sodiumcarbonate and water to neutral, dried and evaporated to dryness. Theresidue consisted of 3fi,20- diacetoxy-A -9/8,10a-pregnadiene which wasutilized in the following step without purification.

6 g. of this crude product were treated with 480 cc. of a 1.2 molarsolution of perbenzoic acid in benzene (2.2 molar equivalents), at roomtemperature and in the dark, for 20 hours. Water was then added, theorganic layer separated, washed with an aqueous solution of sodiumbicarbonate, then with water, dried with anhydrous sodium sulfate andevaporated to dryness. The residue consisted of a mixture of3fi-20-diacetoxy, Sa,6a; 17a,20a-bis-oxido- 9,5,l()apregnane and the5fl,6p-oxido isomer thereof.

This crude mixture was treated with 500 cc. of a 1% methanolic solutionof potassium hydroxide at room temperature for 1 hour, the mixture wasneutralized by addition of acetic acid, concentrated to small volumeunder reduced pressure, the product was precipitated by addition of icewater, filtered off, washed with water, and dried thus giving a mixtureof Sa,6a-oxido-9;8,10a-pregnane-3B,l7a-diol-20-one and the 56,6,8-oxidoisomer thereof.

To 5 g. of the above mixture in 80 cc. of glacial acetic acid, there wasadded a mixture of 6 g. of sodium iodide, 1.6 g. of sodium acetate, 320mg. of zinc and 2 drops of water. While cooling in an ice bath andstirring, there were added to the resulting mixture, 800 mg. of zincdust in small portions. The stirring was continued for 6 hours and thetemperature allowed to attain C.

The reaction mixture was filtered and the filtrate diluted with icewater, alkalized with sodium bicarbonate and extracted with ethylacetate. The extract was washed to neutral, dried over anhydrous sodiumsulfate and evaporated to dryness. Crystallization from acetone-hexaneyielded A -9B,l0a-pregnene-3fl,l7a-diol-20-one.

To a solution of 4.5 g. of the foregoing compound in 100 cc. ofanhydrous benzene there were added 1 g. of p-toluenesulfonic acid and 10cc. of acetic anhydride and the mixture was allowed to stand for 24hours at room temperature, poured into ice and water, and the resultingmixture stirred to effect hydrolysis of the excess anhydride. Thebenzene layer wa separated and washed with 10% sodium carbonate solutionand water. Drying, evaporation and crystallization of the residue frometherhexane produced A -9B,1Oa-pregnene-3B,l7u-diol-20-one-3,17-diacetate.

2 g. of the foregoing diacetate was dissolved in 50 cc. of methanol andtreated with 5 cc. of a 4% aqueous solution of potassium hydroxide; thereaction mixture was stirred for 1 hour under an atmosphere of nitrogenat 0 C.; the mixture was neutralized with acetic acid and the methanoldistilled under reduced pressure. The residue was triturated with waterand the solid collected, washed with water, dried and reclystallizedfrom ethyl acetatemethanol, thus producing A-9p,1()u-pregnene-3B,17adiol-20-one-17-acetate.

Example X The foregoing compound was treated following the proceduredescribed in Example VI, thus yielding 3(3- fluoro-17a-acetoxy-A-9fi,10a-pregnen-20-one.

Example XI A -9fi, 1 Oa-pregnene-3l8, 17adiol-20-one-17-:acetate wastreated in accordance with Example VII, thus furnishing3B-chloro-17a-acetoxyA -9,9,10a-pregnen-20-one.

Example XII Upon treatment of A -9fl,l0a-pregnene-3fi,17oz-diol-20-one-17-acetate by the procedure described in Example VIII there wasobtained 313-bromo-17a-acetoxy-A -9B,10apregnen-ZO-one.

Example XIII A cooled solution of 4 g. of 3B-fiuoro-A-9fiJOa-pregnen-20-one in 30 cc. of tetrahydrofuran and 18 cc. ofmethanol was treated under continuous stirring with 6 g. of pure calciumoxide, in small portions, and then with 6 g. of iodine. The stirring wascontinued at room temperature until the solution turned pale yellow. Themixture was poured into ice water containing 18 cc. of acetic acid and 2g. of sodium thiosulfate. After stirring for 15 minutes the solution wasdecanted and the precipitate was collected by filtration, thus giving 38-fluoro-21-iodo-A 9fi,10a-pregnen-20-one.

The foregoing crude compound was mixed with cc. of acetone and 12 g. ofrecently fused potassium acetate and the mixture was refluxed for 8hours, concentrated to a small volume, diluted with water and extractedwith ethyl acetate; the extract was washed with water, dried overanhydride sodium sulfate and concentrated until crystallization started.The precipitate was collected and crystallized from methanol-water, thusyielding 3,8- fluor0-A -9fi,1Ou-pregnen-Z1-ol-20-one-acetate.

Example XIV 3/3-chloro-A -9/8,10a-pregnen-20-one was treated by theprocedure described in the foregoing example, thus afiordingconsecutively 3fi-chloro-2l-iodo-A -9B,loa-pregnen- 20-one and 33-chloro-A -9B,10a-pregnen-21-ol-2O-one acetate.

Example XV 3fl-bromo-A -9B,IOa-pregnen-ZO-one was treated in accordancewith Example XIII, yielding successively 3/8- bromo-2l-iodo-A-9fl,1Oa-pregnen-2O-one and 3,8-brom0- A-9,B,10a-pregnen-21-ol-20-one-acetate.

Example XVI Following the procedures described in Example XIII, therewas treated 3,3-fiuoro-17a-acetoxy-A -9 8,IOa-pregnen-20-one, thusfurnishing consecutively 3B-fluoro-2l- =iOd0-17a-acet0Xy-A-9fl,1Ooc-p16g116I1-20-Ofle and 3 B-fiuoro- 17a,21-diacetoxy-A-9,8,lOa-pIegnenQO-One.

Example XVII When applying the methods described in Example XIII to3B-chloro-17aacetoxy-A -9B,lOa-pregnen-20-one, there were successivelyobtained 3,8-chloro-21-iodo-17u-acet0xy- A -9B,l0a-pregnen-2O-one, and3/3-chloro-l7a,21-diacetoxy-A -9/3,1Oa-pregnen-2O-one.

Example XVIII 3 ,8 bromo-17a-acetoxy-A -95,10a-pregnen-2O-one wastreated in accordance with the procedures described in Example XIII,thus affording consecutively 3,8-bromo- 2l-iodo-17a-acetoxy-A-9B,lOa-pregnen 20 one and 3B- bromo+17u,2l-diacetoxy-A-9fi,10a-pregnen-20-one.

Example XIX A 95,IOm-pregnen-ZO-One.

When applying the foregoing procedure to the starting compounds under I,there were obtained the corresponding products under II.

Example XX A solution of 0.17 g. of potassium hydroxide in 0.2 cc. ofwater and 2.5 cc. of methanol was added over 30 minutes to a boilingsolution of 1 g. of 3,8-fluoro-17eacetoxy-A -9[3,IOa-pregnen-ZQ-One in30 cc. of methanol under an atmosphere of nitrogen. Boiling wascontinued for a further 2 hours and the solution was then cooled,neutralized with acetic acid and concentrated under reduced pressure.Addition of water, followed by crystallization of the precipitated solidfrom acetone-hexane, produced 3fi-fiuoro-A-9B,lOa-pregnen-17u-ol-20-one.

The starting compounds listed under I were treated following the abovetechnique, thus yielding the corresponding products under H.

I II

Example XXI When applying the above procedure to the starting compoundsunder I there were obtained the products under II.

I II

313 chloro A 913, 10a pregnen- 17 propionate of 3B chloro A 9,8,

17a-0l-20-0ne. 10a-pregncn47a-ol-20-one. 3B bromo A 96, 10a pregnen- 17propionate of 3B bromo A 9H,

17a-ol-20-o11e 1Oa-pregnen-17a-0l-20-one.

3B, 21 difluoro -A 5 9B, 100: preg- 17-propionate of 3B, 21-difluoro-A-9B,

nen-17a-0L20-one. 10a-pregnen-17a-ol-20-one.

3B chloro 21 fll10l0-A -9B, 1004- 17 propionate of 3B cnloro 21-fluoropregnen-17a'0l-20-one. A -9B, 10a-pregnen-17a-0l-20-0ne.

3/3 bromo 21 fiuoro A 17-propionate of3fl-bromo-21-flu0rol0a-pregnen-17a-0l-2O-one. A fl,lOa-pregnen-l7a-ol-20-one 3,8 fluoro A 915, 10a pregnen- 17,21-dipropionate of 3fl-fiu0r0-A -9B,

17a, 21-diol-20-one. 10a-pregnen-17a, 21-diol-20-0ne.

3B chloro A 9B, pregnen- 17, zl-dipropionate of 3,3-chloro-A -9B,

17a. 21-diol-20-one. IOa-pregnen-UB, 2l-diol-20-one.

3 8 bromo A 9,3, 100! pregnen- 17, 21-dipr0pionate of 3B -bromo-A -9fl,

17a, 21-diol-20-one. 10apregnen-17a, 21-d10l-20-one.

Example XXII The starting compounds of the foregoing example weretreated following the procedure described in the same example, exceptthat propionic anhydride was substituted by caproic anhydride andcyclopentylpropionic anhydride, thus affording the correspondingcaproates and cyclopentylpropionates of the said compounds.

Example XXIII A mixture of l g. of 3fi-fiuoro-A-9fl,lOa-pregnen-Zlol-20-one, 4 cc. of pyridine and 2 cc. of propionicanhydride was kept at room temperature overnight, poured into ice water,the formed precipitate was filtered, washed with water and dried.Crystallization from acetonehexane gave the 2l-propionate of3/3-fluoro-A -9B,1Oapregnen-Zl-ol-ZO-one.

The starting compounds under I were treated by the above procedure,yielding the products under H.

I II

35 chloro A 9B, 1001 pregnen- 21-pr0pionate of 38-ehl0ro-A -9B,10a-

21-ol20-one. pregnen-21-ol-20-one. 3B- bromo A 96, 10apregnen-21-propionate of 3Bbr0mo-A -95,10a-

21-ol-20-one. pregnen-21-ol-20-one.

313 fiuoro A 98, 10a pregnan- 17a, 2l-diol-20one.

3B chloro A 9B, 1011 pregnen- 171, 21-diol-20-one.

36 bromo A 93, 10a pregnon- 17oz, 21diol-20-one.

Example XXIV wherein X is selected from the group consisting of'fluorine, chlorine and bromine; Y is a member of the group consisting ofhydrogen, fluorine, hydroxyl and a hydrocarbon carboxylic acyloxy groupof less than 12 carbon atoms'and R is selected from'the group consistingof hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of lessthan 12 carbon. atoms.

1. A COMPOUND OF THE FOLLOWING FORMULA: